Clinical evidence demonstrates that seizures in infants and children cause long-term learning disabilities. However in laboratory studies, the proposed mechanisms for this are inconsistent, partly due to different experimental paradigms. Synaptic properties mediating learning and memory (long-term potentiation (LTP) and long-term depression (LTD)) change with development. These processes involve alterations in glutamate receptor (GluR) subunits that are triggered by specific NMDA receptor (NR) subunits. Our behavioral data demonstrate that a single episode of early-life seizures (ELS) in rats causes later learning disability. This occurs without alteration of neuronal morphology and connections. In vitro studies show alterations in hippocampal LTP and LTD that are consistent with abnormal regulation of glutamate receptors. Contrary to prior biochemical studies suggesting isolated down-regulation of GluR2, our electrophysiological data suggests synaptic GluR1 is transiently up-regulated shortly after ELS but later held in internal pools. Total expression of NR2A becomes permanently decreased. We hypothesize that the transient up-regulation of GluR1 consolidates an abnormal developmental trajectory. This trajectory leads to further abnormal regulation of GluR1 and NR2A that subsequently mediates the abnormal LTP and LTD and the learning disability that we observe following ELS. Abnormal expression of sub-synaptic machinery regulates these alterations in GluR1 and NR2A and hard-wires the long term effects. Currently, there are no therapeutic interventions clinically available for this common, debilitating and costly condition. Thorough characterization of both what makes immature excitatory synapses vulnerable to early-life seizures and the resulting long lasting changes will provide valuable insight into this deficiency as well as the neurobiology of developing synapses. To test our hypothesis and resolve contrary observations we propose three Specific Aims involving in vitro electrophysiological and biochemical studies in rats: Specific Aim 1 (SA1): Expression of homomeric GluR1 receptors early in development makes CA1 hippocampal synapses vulnerable to ELS. Specifc Aim 2 (SA2): ELS causes a rapid, persistent alteration of expression of GluR1 and NR2A receptors that is contrary to normal development. Specific Aim 3 (SA3): The persistent alteration of expression of GluR1 and NR2A receptors following ELS is mediated by altered expression of sub-synaptic machinery. These Aims will provide the evidence necessary to support future R01-funded mechanistic studies that address pharmacological interventions that could prevent the effects of ELS on learning impairment.